Diabetes mellitus, and its systemic and ophthalmic complications, represent an enormous public health threat in the United States. According to the CDC, the number of Americans diagnosed with diabetes has increased from approximately 8.1 million people in 1994 to approximately 17.9 million people in 2007. All patients with diabetes are at risk of developing some form of diabetic retinopathy, an ophthalmic complication of diabetes that presents with symptoms including the swelling and leakage of blood vessels within the retina or the abnormal growth of new blood vessels on the surface of the retina. According to the American Diabetes Association, in the United States diabetic retinopathy causes approximately 12,000 to 24,000 new cases of blindness each year making diabetes the leading cause of new cases of blindness in adults aged 20 to 74. Diabetic Macular Edema (DME), the primary cause of vision loss associated with diabetic retinopathy, is a disease affecting the macula, the part of the retina responsible for central vision. When the blood vessel leakage of diabetic retinopathy causes swelling in the macula, the condition is called DME. The onset of DME is painless and may go undetected by the patient until it manifests with the blurring of central vision or acute vision loss. The severity of this blurring may range from mild to profound loss of vision. The Wisconsin Epidemiologic Study of Diabetic Retinopathy found that over a ten-year period approximately 19% of diabetics studied were diagnosed with DME. As the population of diabetics increases, it is expected that the annual incidence of diagnosed DME will increase.
The current standard of care for the treatment of DME is laser photocoagulation. Laser photocoagulation is a retinal procedure in which a laser is used to cauterize leaky blood vessels or to apply a pattern of burns to reduce edema. This procedure has undesirable side effects including partial loss of peripheral and night vision. As a result of these side effects and a desire for improved visual outcomes, retinal specialists have supplemented laser photocoagulation with alternate off-label therapies for the treatment of DME, including injections of corticosteroids and anti-VEGF agents. Corticosteroids have been shown to improve visual acuity in DME patients in non-pivotal clinical trials, but are associated with increased intraocular pressure (IOP), which may increase the risk of glaucoma and cataract formation. Both of these alternate therapies are currently limited by a need for multiple injections to maintain a therapeutic effect.
Intravitreal Triamcinolone Acetonide Injections (IVTA) have also been used to treat DME. Triamcinolone acetonide is a corticosteroid administered via an intravitreal injection either as an adjunct to laser photocoagulation or as a stand-alone treatment. Typically administered in a 4,000 microgram (μg) suspension, IVTA is relatively inexpensive and has demonstrated temporary visual improvement and reduction of edema in patients with DME. Due to the potential side effects, including increased IOP, which may increase the risk of glaucoma and cataract formation, as well as the need for multiple injections, the use of IVTA for the treatment of DME is not optimal.
Additionally, a 0.7 mg free-floating, three to five month dexamethasone intravitreal implant is available for the treatment of DME following branch or retinal vein occlusion.
Anti-VEGF Intravitreal Injections have also been used to treat DME. Anti-VEGF therapies are administered via an intravitreal injection. VEGF has been identified as an important mediator in diabetic retinopathy, including DME, and appears to play a role in increasing vascular permeability in this condition. Similar to IVTA, anti-VEGFs require multiple injections, potentially as frequently as once per month, to sustain a therapeutic effect. Studies suggest that, in DME, corticosteroids appear to be therapeutically superior to anti-VEGF therapy.
Additionally, intraocular implants have been used in the treatment of ocular diseases other than DME. An exemplary implant marketed by Bausch & Lomb under the name RETISERT® is a sustained release, intravitreal implant with fluocinolone acetonide (FA) as the active corticosteroid. RETISERT® has been used to treat uveitis. This implant is affixed to the eye at the pars plana and is designed to provide controlled release of FA for approximately two and half years. The implant is available in 0.59 mg and 2.1 mg dosage forms.
A need exists for an effective treatment for ophthalmic complications related to diabetes mellitus that requires fewer injections and reduces the incidence of adverse side effects.